[3 + 2]-Annulation reactions of chiral allylsilanes and chiral aldehydes. Studies on the synthesis of bis-tetrahydrofuran substructures of annonaceous acetogenins

Article abstract of DOI:10.1021/jo0511290

Double asymmetric [3 + 2]-annulation reactions of chiral β-silyloxylallylsilanes with chiral 2-tetrahydrofuranyl carboxaldehydes have been studied, leading to the stereocontrolled synthesis of six diastereomeric bis-tetrahydrofuran structures correspondin

Full text of DOI:10.1021/jo0511290

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Chiral
Aldehydes. Studies on the Synthesis of Bis-tetrahydrofuran
Substructures of Annonaceous Acetogenins
Eric Mertz, Jennifer M. Tinsley, and William R. Roush*,†
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109
roush@scripps.edu
Received June 4, 2005
Double asymmetric [3 + 2]-annulation reactions of chiral â-silyloxyallylsilanes with chiral
2-tetrahydrofuranyl carboxaldehydes have been studied, leading to the stereocontrolled synthesis
of six diastereomeric bis-tetrahydrofuran structures corresponding to the core subunits of members
of the Annonaceous acetogenin family of natural products. Transition-state models are proposed
to account for the stereoselectivity of the double-stereodifferentiating [3 + 2]-annulation reactions.
SCHEME 1
Introduction
Allylsilanes are versatile reagents that participate in
a variety of synthetically important C-C bond-forming
reactions.1 Among these are allylation reactions of car-
bonyl compounds and [3 + 2]-annulation reactions of
carbonyl compounds, imines, and activated double bonds
to form substituted 5-membered ring carbocycles and
heterocycles. Chiral allylsilanes have been utilized in [3
+ 2]-annulation reactions in a number of natural product
total syntheses in recent years.2
We have reported an efficient and enantioselective
synthesis of chiral, nonracemic anti â-silyloxy allylsilanes
1 through the reaction of aldehydes with chiral (E)-γ-
(dimethylphenylsilyl)allylborane reagent 2 (Scheme 1).3
Subsequent treatment of 1 with a second aldehyde in the
† Current Address: Scripps Florida, Medicinal Chemistry, 5353
Parkside Drive, RF-2, Jupiter, FL 33458.
(1) (a) Fleming, I.; Dunogues, J.; Smithers, R. Org. React. 1989, 37,
57. (b) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293. (c)
Kno¨lker, H.-J. J. Prakt. Chem. 1997, 339, 304. (d) Chabaud, L.; James,
P.; Landais, Y. Eur. J. Org. Chem. 2004, 3173.
presence of SnCl4 or BF3‚OEt2 then provides tetrahydro-
furans 3a or 3b with substitution at the 2, 3, and 5
positions.4 Key to this process is the discovery that the
[3 + 2]-annulation reaction of 1 in the presence of BF3‚
OEt2 provides the 2,5-cis-substituted tetrahydrofuran 3b
with excellent selectivity via a nonchelate-controlled
transition state, whereas the reaction of 1 with R-alkoxy-
(2) Examples and lead references include: (a) Peng, Z.-H.; Woerpel,
K. A. Org. Lett. 2001, 3, 675. (b) Roberson, C. W.; Woerpel, K. A. J.
Am. Chem. Soc. 2002, 124, 11342. (c) Peng, Z.-H.; Woerpel, K. A. Org.
Lett. 2002, 4, 2945. (d) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc.
2002, 124, 3608. (e) Peng, Z.-H.; Woerpel, K. A. J. Am. Chem. Soc.
2003, 125, 6018. (f) Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005,
127, 6950.
(3) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett.
2000, 41, 9413.
(4) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461.
10.1021/jo0511290 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/30/2005
J. Org. Chem. 2005, 70, 8035-8046
8035

Mertz et al.
SCHEME 2
CHART 1
substituted aldehydes in the presence of SnCl4 provides
the isomeric 2,5-trans-tetrahydrofuran 3a via a chelate-
controlled transition state.4 Removal of the 3-PhMe2Si
substituent in 3a or 3b by protiodesilylation yields the
2,5-disubstituted tetrahydrofurans 4a and 4b.5 Alterna-
tively, transformation of the PhMe2Si group into a
secondary alcohol can occur via the Tamao-Fleming
oxidation.6 Our laboratory has recently employed our [3
+ 2]-annulation process toward the total synthesis of
several tetrahydrofuran-containing natural products,
including pectenotoxin II, amphidinolide F, and asimicin
(5).7
derived desilylated bis-tetrahydrofurans 9a-f, com-
pounds whose structures are related to the core subunits
of several highly potent antitumor compounds from the
Annonaceous acetogenin family of natural products
(Chart 1).10 During the course of these studies, we
developed a highly stereoselective synthesis of asimicin
5, an Annonaceous acetogenin possessing a trans-threo-
trans bis-tetrahydrofuran core.7c The stereochemical
generality of the [3 + 2]-annulation reaction, and its
potential to access a stereochemically diverse group of
structures from common precursors, makes our approach
a complementary alternative to existing modular syn-
theses of the Annonaceous acetogenins and small librar-
ies of stereochemically diverse bis-tetrahydrofuran sys-
tems.11,12
Relatively few double-stereodifferentiating8 [3 + 2]-an-
nulation reactions of chiral, nonracemic allylsilanes and
chiral aldehydes have been reported. Panek reported
examples of double asymmetric [3 + 2]-annulation reac-
tions of (S)-2-(benzyloxy)propanal with two enantiomeric
chiral crotylsilanes.9 Woerpel has disclosed examples of
kinetic resolution involving [3 + 2]-annulation reactions
of chiral aldehydes and racemic allylsilanes.2c,e We report
herein an investigation of double-stereodifferentiating [3
+ 2]-annulation reactions of a pair of enantiomeric chiral
allylsilanes 6a and 6b with chiral tetrahydrofuranyl
aldehydes 7a and 7b (Scheme 2). This study was stimu-
lated by our interest in developing a stereochemically
general synthesis of bis-tetrahydrofurans 8a-f and the
Results
Chiral allylsilane 6a was synthesized through the
reaction of undecanal 12 with (E)-γ-[(dimethylphenylsi-
(10) (a) Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.;
Cortes, D. Phytochemistry 1998, 48, 1087. (b) Alali, F. Q.; Liu, X.-X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. (c) Wang, X.-W.; Xie,
H. Drugs Future 1999, 24, 159.
(11) (a) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S.
J. Org. Chem. 1995, 60, 4419. (b) Hoye, T. R.; Tan, L. Tetrahedron
Lett. 1995, 36, 1981. (c) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.;
Keinan, E. Tetrahedron Lett. 1995, 36, 9257. (d) Sinha, S. C.; Sinha,
A.; Yazbak, A.; Keinan, E. J. Org. Chem. 1996, 61, 7640. (e) Marshall,
J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62, 5989. (f) Marshall, J. A.;
Jiang, H. J. Org. Chem. 1999, 64, 971. (g) Emde, U.; Koert, U. Eur. J.
Org. Chem. 2000, 1889. (h) A modular approach to sixteen diastere-
omeric mono-tetrahydrofuran Annonaceous acetogenins has been
recently disclosed in: Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J.
Am. Chem. Soc. 2004, 126, 36.
(12) (a) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Soc. 1985, 107,
5312. (b) Hoye, T. R.; Suhadolnik, J. C. Tetrahedron 1986, 42, 2855.
(c) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 61, 4247. (d)
Figade´re, B.; Peyrat, J.-F.; Cave`, A. J. Org. Chem. 1997, 62, 3428. (e)
Keinan, E.; Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C. Pure Appl.
Chem. 1997, 69, 423. (f) Bruns, R.; Kopf, J.; Ko¨ll, P. Chem. Eur. J.
2000, 6, 1337. (g) Kojima, N.; Maezaki, N.; Tominaga, H.; Yanai, M.;
Urabe, D.; Tanaka, T. Chem. Eur. J. 2004, 10, 672.
(5) (a) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem.
Soc. 1982, 104, 6809. (b) Hudrlik, P. F.; Holmes, P. E.; Hudrlik, A. M.
Tetrahedron Lett. 1988, 29, 6395. (c) Heitzman, C.; Lambert, W. T.;
Mertz, E.; Shotwell, J. B.; Tinsley, J. M.; Va, P.; Roush, W. R. Org.
Lett. 2005, 7, 2405.
(6) Review on oxidation of C-Si bonds: Jones, G. R.; Landais, Y.
Tetrahedron 1996, 52, 7599.
(7) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. (b)
Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865. (c) Tinsley, J.
M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818.
(8) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(9) Panek, J. S.; Beresis, R. J. Org. Chem. 1993, 58, 809.
8036 J. Org. Chem., Vol. 70, No. 20, 2005

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Aldehydes
SCHEME 3
SCHEME 4
SCHEME 5
lyl)allyl]diisopinocampheylborane (derived from (-)-Ipc2-
BOMe and allyldimethylphenylsilane, Scheme 3).3,7c The
absolute configurations and enantiopurity of 6a and its
enantiomer 6b (derived from (+)-Ipc2BOMe and allyldim-
ethylphenylsilane, Scheme 4) were determined through
Mosher ester analysis of the corresponding secondary
alcohols.13,14 Treatment of 6a with R-(benzyl-
oxy)acetaldehyde 13 in the presence of either SnCl4 or
BF3‚OEt2 gave the 2,5-trans-tetrahydrofuran 14a and the
2,5-cis-tetrahydrofuran 14b, respectively (Scheme 3). The
relative stereochemistry at the C2 and C5 positions in
14a and 14b were assigned using 1H NOE analysis,
consistent with our previously reported synthesis of 2,3,5-
trisubstituted tetrahydrofuran rings.4,13 The relative con-
figuration about the C2-CR bond in 14a and 14b was
assigned as threo on the basis of our previous findings
that the threo relationship at this position results from
[3 + 2]-annulation reactions of â-silyloxyallylsilanes with
anti relative stereochemistry (e.g., allylsilanes 6a and
6b).4
In our total synthesis of asimicin 5, the 2,5-trans-
tetrahydrofuryl aldehyde 15a, which was synthesized
from 14a (Scheme 3), underwent a SnCl4-catalyzed [3 +
2]-annulation reaction with the chiral allylsilane 16 to
form the trans-threo-trans core 17 in 80% yield with
excellent diastereoselectivity (Scheme 5).7c To explore
extensions of this iterative [3 + 2]-annulation strategy
in the synthesis of additional bis-tetrahydrofuran stereo-
isomers, allylsilane 6a was employed as a simplified
analogue of 16. The BF3‚OEt2-catalyzed [3 + 2] annula-
tion reaction of 6a with 15a afforded the trans-erythro-
cis bis-tetrahydrofuran structure 18a in 25% yield as the
only bis-tetrahydrofuran product (Scheme 6).
The stereochemistry of 18a was assigned through
1
inspection of its H and 13C NMR spectra. Six separate
methine resonances were observed consistent with an
unsymmetric structure. The absolute configurations of
the two stereogenic centers flanking the bis-tetrahydro-
furan moiety (C6 and C6′) are known to be R from
Mosher ester analysis of the parent allylsilane 6a. It is
also known from the stereochemistry of the parent
aldehyde 15a that one of the tetrahydrofuran rings in
18a is a 2,5-trans-substituted ring and that a threo
relationship exists between the C5 and C6 substituents.
Given this information, there is no unsymmetric struc-
ture other than the trans-erythro-cis structure 18a, which
could result from the BF3‚OEt2-catalyzed [3 + 2]-annu-
lation between 6a and 15a.
The [3 + 2]-annulation reactions of the 2,5-cis-tetrahy-
drofuryl aldehyde 15b with allylsilane 6a were also
attempted; however, neither the BF3‚OEt2-catalyzed
(13) See the Supporting Information.
(14) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
J. Org. Chem, Vol. 70, No. 20, 2005 8037

Mertz et al.
SCHEME 6
FIGURE 1. Comparison of proposed conformations of the
trisubstituted tetrahydrofuryl aldehydes 15a/15b with con-
formations for 7a/7b.
SCHEME 7
between the C5 and C6 substituents. Thus, there is no
symmetric structure other than the cis-erythro-cis struc-
ture 18b which could result from a [3 + 2]-annulation
between 15b and 6b.
MM2 energy minimization calculations suggested that
the carbonyl group in the 2,5-cis-tetrahydrofuryl alde-
hyde 15b is quite sterically encumbered due to its close
proximity to the CR substituent (Figure 1). Nonbonded
interactions between the aldehyde and the CR substitu-
ent result from a puckered conformation of the tetrahy-
drofuran ring; this conformation presumably is adopted
in order to minimize gauche interactions between the C5-
alkyl substituent and the large C4-phenyldimethylsilyl
group. The aldehyde carbonyl group in the 2,5-trans-
tetrahydrofuryl aldehyde 15a is also thought to be
sterically hindered, although less severely. In the case
of 15a, nonbonded interactions arise between the carbo-
nyl group and the C4-phenyldimethylsilyl substituent.
It was proposed that the tetrahydrofuran ring in the
disubstituted aldehydes 7a and 7b would exist in a more
planar conformation, relieving steric hindrance of the
aldehyde carbonyl groups and thus increasing their
reactivity in the [3 + 2]-annulation reaction. Accordingly,
7a and 7b were synthesized by first subjecting 14a and
14b to protiodesilylation mediated by tetrabutylammo-
nium fluoride (TBAF) in a THF-DMF mixture to give
19a and 19b (Scheme 7).5 Removal of the benzyl ether
protecting group by catalytic hydrogenolysis, followed by
oxidation of the resulting primary alcohol provided the
2,5-trans- and 2,5-cis-disubstituted tetrahydrofuryl al-
dehydes 7a and 7b.
reaction nor the SnCl4-catalyzed reaction reliably gave
bis-tetrahydrofuran products. Instead, a complex mixture
of unidentified decomposition products was obtained.
However, [3 + 2]-annulation reactions of 15b and the
enantiomeric allylsilane 6b furnished [3 + 2]-annulation
products under both chelation- and nonchelation-con-
trolled conditions (Scheme 6). Surprisingly, both the BF3‚
OEt2- and SnCl4-catalyzed reactions gave the cis-erythro-
cis stereoisomer 18b as the major product. Particularly
striking was the fact that the SnCl4-mediated annulation
produced a 2,5-cis-substituted tetrahydrofuran ring, con-
trary to our previous results of chelation controlled [3 +
2]-annulations involving achiral aldehydes.4 Reaction of
6b and the 2,5-trans-aldehyde 15a in the presence of
either BF3‚OEt2 or SnCl4 gave largely decomposition
products and trace (<5%) amounts of [3 + 2]-annulation
products.
The stereochemistry of the bis-tetrahydrofuran 18b
was again assigned through inspection of its 1H and 13
C
NMR spectral data. Only three separate methine reso-
nances exist for 18b, consistent with a meso or C2-
symmetric structure. The R absolute configuration of C6
in 18b is known from the stereochemistry of 6a, the
parent allylsilane employed in the synthesis of aldehyde
15b. Likewise, the S configuration of C6′ is known from
Mosher ester analysis of the â-hydroxyallylsilane precur-
sor to 6b. We also know that one of the tetrahydrofuran
rings in 18b possesses the 2,5-cis stereochemistry present
in aldehyde 15b, and a threo relationship is known
The 2,5-trans-tetrahydrofuryl aldehyde 7a underwent
a [3 + 2]-annulation with 6a in the presence of SnCl4 at
0 °C to give the bis-tetrahydrofuran diastereomer 8a with
high stereoselectivity (Scheme 8). The trans-threo-trans
8038 J. Org. Chem., Vol. 70, No. 20, 2005

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Aldehydes
SCHEME 8
SCHEME 9
The R configuration at C6 and the S configuration at C6′
were known from the allylsilane precursors to 8c, and
the stereochemistry of aldehyde 7a established one ring
in 9c to have 2,5-trans stereochemistry with a threo
relationship between the C5 and C6 substituents. All of
this evidence initially pointed to the trans-erythro-trans
stereochemistry shown in 8g and 9g. However, the 13C
NMR data for 9c did not unambiguously indicate a
symmetric compound, and further stereochemical cor-
relation studies, to be discussed in a subsequent section,
confirmed the trans-threo-cis stereochemistry for 8c and
9c.
Reactions of the 2,5-cis-tetrahydrofuryl aldehyde 7b
with both enantiomeric allylsilanes 6a and 6b were also
stereoconvergent under chelation-controlled and non-
chelation-controlled [3 + 2]-annulation conditions (Scheme
10). The [3 + 2]-annulation of 7b with 6b gave the cis-
erythro-cis isomer 8d preferentially in the presence of
either SnCl4 or BF3‚OEt2. Protiodesilylation of 8d re-
vealed the symmetric bis-tetrahydrofuran 9d, which
exhibits only three nonequivalent methine resonances in
its 1H and 13C NMR spectra. The R absolute configuration
of C6 in 9d is known from the stereochemistry of the
parent allylsilane employed in the synthesis of aldehyde
7b. Likewise, the S configuration of C6′ is known from
allylsilane 6b. We also know that one tetrahydrofuran
ring in 9d possesses the 2,5-cis stereochemistry present
in aldehyde 7b, and a threo relationship is known
between the C5 and C6 substituents. Thus, there is no
symmetric structure other than the cis-erythro-cis struc-
ture that can be assigned for 9d.
stereochemistry of 8a was determined through protio-
desilylation to afford the bis-tetrahydrofuran 9a. This
compound exhibited only three methine resonances in its
13C and 1H NMR spectra, indicative of a symmetric
structure. Because both the C6 and C6′ are known to
have the R configuration, and one 2,5-trans-disubstituted
ring with a threo relationship between the C5 and C6
positions is present in 9a, its structure was assigned as
the symmetric trans-threo-trans stereochemistry.15 The
BF3‚OEt2-catalyzed reaction of 7a and 6a afforded a
different bis-tetrahydrofuran product 8b. Protiodesi-
lylation of 8b provided 9b, a bis-tetrahydrofuran with
six separate methine resonances in its 1H and 13C spectra.
The unsymmetric trans-erythro-cis stereochemical rela-
tionship was thus assigned to 8b and 9b.
Reactions of the 2,5-trans-aldehyde 7a with the enan-
tiomeric allylsilane 6b illustrate the improvement in
reactivity which was obtained by removal of the PhMe2-
Si- group from the tetrahydrofuryl aldehyde substrates
(Scheme 9). In this case, the same diastereomer 8c was
obtained when either SnCl4 or BF3‚OEt2 was used as the
Lewis acid catalyst.16 Also noteworthy is the diminished
selectivity for formation of 8c compared to annulations
giving 8a and 8b (Scheme 8). Protiodesilylation of 8c
yielded bis-tetrahydrofuran 9c, which possessed three
While a [3 + 2]-annulation reaction of the 4-PhMe2Si-
substituted 2,5-cis-disubstituted aldehyde 15b with 6a
was not observed, reaction of 7b with 6b resulted in the
cis-erythro-trans bis-tetrahydrofuran 8e using either
Lewis acid catalyst. Protiodesilylation of 8e gave the
unsymmetric bis-tetrahydrofuran 9e which is identical
to 9b, the product obtained from protiodesilylation of 8b.
The fact that both 8b and 8e converge to a single bis-
tetrahydrofuran product upon protiodesilylation provides
additional support for the trans-erythro-cis stereochemis-
1
separate methine resonances in its H NMR spectrum.
(15) 1H and 13C NMR data for compound 9a matched data reported
from previous syntheses of this compound: (a) Rieser, M. J.; Hui, Y.;
Rupprecht, J. K.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.;
Hanson, P. R.; Zhuang, Z.; Hoye, T. R. J. Am. Chem. Soc. 1992, 114,
10203. (b) Naito, H. Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S.
J. Org. Chem. 1995, 60, 4419. (c) Hamada, T.; Naoya, I.; Abe, M.;
Fujita, D.; Kenmochi, A.; Nishioka, T.; Zwicker, K.; Brandt, U.; Miyoshi,
H. Biochemisry 2004, 43, 3651.
(16) The structure of the minor diastereomer product in reactions
of 7a and 6b was not unambiguously determined.
J. Org. Chem, Vol. 70, No. 20, 2005 8039

Mertz et al.
SCHEME 10
SCHEME 11
and allylsilane 6b compared to the reaction of 7c with
6a. In this case, the [3 + 2]-annulation product was taken
directly onto protiodesilylation to form the cis-erythro-
cis bis-tetrahydrofuran product 9d that was also obtained
through the SnCl4-catalyzed reaction of the TBS-protect-
ed tetrahydrofuryl aldehyde 7b and allylsilane 6b (Scheme
10).
To further support our stereochemical assignment of
the bis-tetrahydrofuran stereoisomers, 9a-f were treated
with acetic anhydride in pyridine to obtain five bis-
acetate derivatives 20a-f (Figure 2). Hoye and co-
workers have synthesized acetate derivatives of twelve
diastereomers of related dihexyl-substituted bis-tetrahy-
drofurans with well-defined stereochemistry (i.e., 21a-
f).12a Since the disclosure of Hoye’s study, the stereo-
chemistry of the bis-tetrahydrofuran subunits of several
Annonaceous acetogenins has been assigned by compari-
son of 1H NMR chemical shifts of the peracetylated
natural products with Hoye’s prototype compounds. As
shown in Figure 2, our synthetic bis-acetate derivatives
20a-f match closely with the literature data for 21a-f.
Thus, the stereochemical assignments of 8a-f and 9a-f
were confirmed. In the case of bis-tetrahydrofuran 9c,
conversion to the bis-acetate 20c clearly gave an unsym-
metric compound with six separate methine resonances,
supporting the trans-threo-cis stereochemistry for 9c as
shown in Scheme 9.
try of 9b. We know that 9b contains one 2,5-trans-
disubstituted tetrahydrofuran and one 2,5-cis-disubsti-
tuted tetrahydrofuran ring. Both of the flanking OH
groups in 9b have the R absolute configuration, and these
groups possess threo relationships with their adjacent
stereogenic centers. Consequently, there are no bis-
tetrahydrofuran structures other than 9b that are pos-
sible.
Due to our inability to obtain different stereoisomers
by changing the Lewis acid catalyst in [3 + 2]-annula-
tions reactions of 7b with either allylsilane enantiomer,
we began to explore alternative tactics for achieving
Lewis acid dependent stereodivergence with this sub-
strate. The cis-tetrahydrofuryl aldehyde 7c, which bears
an acetate protecting group adjacent to the tetrahydro-
furan ring rather than a TBS group, was synthesized to
examine the effect of subtle structural modifications on
the stereoselectivity of the annulation reaction (Scheme
11).13 Remarkably, the SnCl4-catalyzed reaction between
7c and 6a resulted in a complete reversal in stereo-
selectivity compared to 7b, giving a 7:1 ratio of bis-
tetrahydrofurans 8f and 8e in 57% yield. The BF3‚OEt2
catalyzed reaction of 7c with 6a was not successful,
affording only a low yield of [3 + 2]-annulation products
with poor diastereoselectivity. The cis-threo-cis stereo-
chemistry of 8f was established upon protiodesilylation
to afford 9f, a bis-tetrahydrofuran with 1H and 13C NMR
data indicating a symmetric product. The R configuration
at the 6 and 6′ positions in 9f are known, and one 2,5-
cis-tetrahydrofuran ring must be present in the structure.
There are no other possible symmetric stereochemical
assignments for 9f other than the cis-threo-cis structure
shown.
Discussion
The results described above demonstrate that the
paradigm governing stereoselectivity for [3 + 2]-annu-
lation reactions of chiral allylsilanes with achiral alde-
hydes (i.e., that SnCl4 provides 2,5-trans-substituted
tetrahydrofurans via chelation controlled and BF3‚OEt2
gives 2,5-cis-substituted tetrahydrofurans via nonchelate
controlled pathways) does not always predict the outcome
of double-stereodifferentiating [3 + 2]-annulation reac-
tions involving chiral tetrahydrofuryl aldehydes and
chiral allylsilanes. Examination of possible transition
states of each annulation process provides insight into
the factors that may govern the stereochemical outcome
of these reactions.
No reversal in diastereoselectivity was observed in the
SnCl4-catalyzed [3 + 2]-annulation reaction between 7c
8040 J. Org. Chem., Vol. 70, No. 20, 2005

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Aldehydes
1
FIGURE 2. Synthesis of bis-acetate derivatives 20a-f and comparison of H NMR data for 20a-f with literature data12a for
related bis-tetrahydrofuran acetate derivatives 21a-f.
We have previously proposed that the [3 + 2]-annula-
tion of chiral allylsilanes with aldehydes proceeds through
syn-synclinal transition states (shown as I and II for
reaction of 6a with 13) in order for favorable electronic
interactions between the two coupling partners to be
optimized (Figure 3).4,17,18 We suggest that the most
sterically demanding quadrant of these structures is that
occupied by the Lewis acid. Accordingly, SnCl4 and BF3‚
OEt2 give rise to different syn-synclinal transition states
based on the different geometry of the Lewis acid-
aldehyde complex in the two transition states.
FIGURE 3. Proposed syn-synclinal transition states for the
(17) The importance of syn-synclinal transition states for additions
[3 + 2]-annulation of 6a with an achiral aldehyde. Shown are
transition states for reaction of 6a with 13 to form mono-
tetrahydrofurans 14a and 14b.
of type II allylmetal reagents to aldehydes has been supported by
experimental and theoretical studies in: (a) Keck, G. E.; Savin, K. A.;
Cressman, E. N. K.; Abbott, D. E. J. Org. Chem. 1994, 59, 7889. (b)
Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Willson, T. M. Tetrahedron
1989, 45, 1053.
(18) Other transition-state models have been proposed. Panek has
proposed several [3 + 2]-annulation reactions to proceed through
antiperiplanar transition states: Panek, J. S.; Yang, M. J. Am. Chem.
Soc. 1991, 113, 9868. Our laboratory has previously proposed the
possibility of a synclinal addition mode.4
For [3 + 2]-annulation reactions involving chiral R-tet-
rahydrofuryl aldehydes 7a and 7b, the inherent dia-
stereofacial preference of nucleophilic attack under che-
J. Org. Chem, Vol. 70, No. 20, 2005 8041

Mertz et al.
lation and nonchelation control must also be considered;
the Cram chelate and Felkin models for carbonyl addition
can be used to predict the facial bias of aldehydes 7a and
7b.19 The stereoselectivity of substrate-controlled addi-
tions of achiral organometallic reagents to R-tetrahydro-
furyl aldehydes under chelating and nonchelating con-
ditions has been reported by several groups.20 In general,
2,5-trans-disubstituted tetrahydrofuryl aldehydes analo-
gous to 7a exhibit the expected reversal of π-facial
selectivity depending on chelation- or nonchelation-
controlled conditions. These substrates achieve excellent
induction via chelation control and moderate Felkin
selectivity via nonchelation control. Conversely, 2,5-cis-
disubstituted tetrahydrofuryl aldehydes similar to 7b
achieve excellent Felkin selectivity in the presence of
nonchelating Lewis acids, but they have not furnished
the complementary Cram chelate addition products
expected in the presence of SnCl4.20d,i
For the SnCl4-catalyzed reaction of 7a with 6a, ap-
proach of the allylsilane to the re face of the Lewis acid
complexed aldehyde (transition state IIICram) is preferred
by the Cram chelate model (Figure 4). Transition state
IIICram also minimizes steric interactions between 6a and
SnCl4. This reaction can be considered a case of matched
double stereodifferentiation, a conclusion consistent with
the high level of stereoselectivity observed for the forma-
tion of the product 8a. For the BF3‚OEt2-catalyzed [3 +
2]-annulation reaction of 7a with 6a, approach of the
allylsilane to the si face of 7a is predicted by the Felkin
model, as illustrated by structure IVFelkin. Because the
Felkin transition state also minimizes steric interactions
between the sterically large side chain of 6a and BF3,
this reaction can also be viewed as a case of matched
double stereodifferentiation. As a result, the bis-tetrahy-
drofuran product 8b is formed with very high diastereo-
selectivity.
FIGURE 4. Proposed transition states for the chelation and
nonchelation controlled [3 + 2]-annulations of 6a and the 2,5-
trans-disubstituted tetrahydrofuryl aldehyde 7a.
In the SnCl4-catalyzed reaction of 7a with the enan-
tiomeric allylsilane 6b, syn-synclinal approach of the
least hindered face of the allylsilane to the Cram chelate
predicted re face of 7a results in transition state
tures are highly disfavored due to attack at the more
hindered face of the SnCl4-chelated aldehyde.
The BF3‚OEt2-catalyzed reaction of 7a with 6b is also
considered to be a mismatched double-asymmetric reac-
tion (Figure 6). As illustrated by VIIIFelkin, syn-synclinal
attack of 6b at the Felkin-predicted si face of 7a is
sterically disfavored, and product 8g is thus not isolated.
Instead, 8c, the product of addition of 6b to the anti-
Felkin face of 7a, is obtained. Transition states VIIsyn-synclinal
or VIIsynclinal must be operative in order to form 8c in this
reaction. The stereochemical mismatch of 7a and 6b is
evident in the reduced levels of stereoselectivity in the
reactions of these two substrates, and reduced product
yields, a consequence of more side products of allylation
and other minor reaction pathways. The magnitude in
the difference in energy between transition states
VIIsyn-synclinal and VIIsynclinal and competing pathways is
likely not as great as in the matched double-stereodif-
ferentiating reactions.
The stereoconvergent nature of the SnCl4 and BF3‚
OEt2-catalyzed reactions of 7a with 6b was puzzling, but
not without precedent. In Panek’s study of double-
stereodifferentiation in the [3 + 2]-annulation reaction,
an apparently mismatched reaction of a chiral crotyl-
silane with (S)-benzyloxypropanal afforded the same
tetrahydrofuran stereoisomer in the presence of either
SnCl4 or BF3‚OEt2.20d,i Similar to our results, Panek
V
syn-synclinal, which would experience unfavorable steric
interactions in the quadrant containing the Lewis acid
(Figure 5). Consequently, this reaction is viewed as a
mismatched double-asymmetric reaction, and transition
state Vsyn-synclinal is likely a disfavored structure. The
synclinal transition state Vsynclinal, which leads to the
observed product 8c, should be a favorable reaction
pathway due to reduced nonbonded interactions and
attack of the allylsilane to the Cram chelate face of 7a.
Two alternative transition states, the anti-Cram syn-
synclinal structure VIsyn-synclinal and the antiperiplanar
structure VIanti-periplanar both lead to the unobserved bis-
tetrahydrofuran product 8g. These transition-state struc-
(19) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748. (b) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1967,
2199. (c) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
(20) (a) Williams, D. R.; Harigaya, Y. L.; Moore, J. L.; D’Sa, A. J.
Am. Chem. Soc. 1984, 106, 2641. (b) Koert, U.; Stein, M.; Harms, K.
Tetrahedron Lett. 1993, 34, 2299. (c) Koert, U. Tetrahedron Lett. 1994,
35, 2517. (d) Bradley, G. W.; Thomas, E. J. Synlett 1997, 629. (e) Mori,
Y.; Sawada, T.; Furukawa, H. Tetrahedron Lett. 1999, 40, 731. (f)
Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed. 2000,
39, 3622. (g) Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739.
(h) Maezaki, N.; Kojima, N.; Tominaga, H.; Yanai, M.; Tanaka, T. Org.
Lett. 2003, 5, 1411. (i) Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org.
Lett. 2004, 6, 1895.
8042 J. Org. Chem., Vol. 70, No. 20, 2005

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Aldehydes
FIGURE 5. Proposed transition states for the SnCl4-mediated
[3 + 2]-annulation reaction of 6b and 2,5-trans-tetrahydrofuryl
aldehyde 7a.
FIGURE 6. Proposed transition state for the BF3‚OEt2-
observed that the nonchelate-controlled reaction gave a
product consistent with addition to the anti-Felkin rota-
mer of the aldehyde, suggesting that the enantioselec-
tivity of allylsilane 6b overwhelms the intrinsic facial
bias of aldehyde 7a. A similar phenomenon was observed
in our laboratory during studies of carbonyl addition
reactions of a γ-[(diisopropylidine-R-D-mannopyranosyl)-
oxy]allylstannane21 and also in Ley’s report of Mu-
kaiyama aldol reactions involving chiral silyl enol ether
substituted π-allyltricarbonyliron complexes.22
catalyzed [3 + 2]-annulation reaction of 6b and the 2,5-trans-
disubstituted tetrahydrofuryl aldehyde 7a.
“matched case”, is consistent with other reports of Lewis
acid catalyzed reactions of 2,5-cis-substituted tetrahy-
drofuran aldehydes with allylsilanes and allylstan-
nanes.20d,i Stereoconvergence of SnCl4- and BF3‚OEt2-
catalyzed additions of group II allylmetal reagents to
these substrates is a general phenomenon. In solution
with SnCl4, aldehyde 7b must exist in a rapid equilibrium
between the chelated structure 7bchelate and the non-
chelated structure 7bnonchelate (Figure 8). The nonchela-
tion-controlled transition state XFelkin must be sufficiently
low in energy so that product 8d forms nearly exclusively.
Our proposal of a rapid equillibrium between 7bchelate
and 7bnon-chelate is in opposition to the conventional
prediction of highly robust complexes forming between
chelating Lewis acids and R- and â-alkoxy-substituted
aldehydes.23 However, spectroscopic evidence, crystal-
lographic data, and experimental results have indicated
that mixtures of SnCl4- and â-alkoxy-substituted alde-
hydes can exist in equilibrium between the bidentate
chelated aldehyde and the nonchelated aldehyde.24 This
equilibrium is highly dependent on the structure of the
aldehyde substrate, and the extent to which the bidentate
For the nonchelation-controlled reaction of 6b with the
2,5-cis-tetrahydrofuryl aldehyde 7b, syn-synclinal ap-
proach of the allylsilane to the si face of the aldehyde is
preferred (transition state IXFelkin), and this trajectory
does not exhibit significant steric crowding between
allylsilane 6b and BF3 (Figure 7). Structure IXFelkin which
leads to 8d, thus represents a matched transition state
for the 2,5-cis-tetrahydrofuryl aldehyde. For the SnCl4-
mediated reaction, structure XCram, in which the Cram
chelate face of 7b is approached by 6b, was expected to
be the major reaction pathway. However, the major
product observed for the SnCl4-catalyzed annulation,
compound 8d, does not arise from this transition state.
Thus, aldehyde 7b must react through a monodentate
complex with SnCl4, as shown by transition state XFelkin
.
Our finding that the SnCl4-catalyzed reaction of 6b and
7b favors the “anti-Cram” product 8d, even for the
(22) Ley, S. V.; Cox. L. R.; Worrall, J. M. J. Chem. Soc., Perkin
Trans. 1 1998, 3349.
(23) Review of chelation-controlled carbonyl addition reactions:
Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(21) Roush, W. R.; VanNieuwenhze, M. S. J. Am. Chem. Soc. 1994,
116, 8536.
J. Org. Chem, Vol. 70, No. 20, 2005 8043

Mertz et al.
FIGURE 8. Proposed equilibration between bidentate che-
lated and nonchelated forms of 2,5-cis-disubstituted tetrahy-
drofuryl aldehyde 7b.
expected based on Denmark’s evidence of aldehydes
forming such complexes in the absence of bidentate
chelate formation.17b,27
For the BF3‚OEt2-catalyzed reaction of 7b and 6a, the
Felkin syn-synclinal transition state XIIsyn-synclinal again
suffers from unfavorable steric congestion in the quad-
rant containing the Lewis acid (Figure 9). We therefore
view 7b and 6a as another mismatched pair of reaction
partners. Thus, the observed major product 8e is pro-
posed to form through the Felkin antiperiplanar struc-
ture XIIantiperiplanar, the most sterically accessible transi-
tion state. The anti-Felkin transition states XIsyn-synclinal
and XIsynclinal are apparently disfavored, consistent with
our observations, and the observations of others,20d,i that
additions to 2,5-cis-disubstituted tetrahydrofuryl alde-
hydes occur with a strong sense of Felkin induction.
The SnCl4-mediated [3 + 2]-annulation reaction of 7b
and 6a also furnished 8e with moderate (8:1) diastereo-
selectivity (Figure 10). Addition to the Cram chelate face
of 7b, through transition state XIIIsyn-synclinal or XIIIsynclinal
was initially expected. However, the observed product 8e
forms through addition to the Felkin face of aldehyde 7b.
The two proposed Felkin transition states, XIVantiperiplanar
and XIVsyn-synclinal both invoke simple coordination of 7b
by SnCl4 without formation of a bidentate chelate struc-
ture. The antiperiplanar mode XIVantiperiplanar is favored
because it likely experiences fewer nonbonded interac-
tions than the syn-synclinal transition state. Chelation
control in the [3 + 2]-annulation reaction of 7b with 6a
is disfavored for the same reasons explained above for
the reaction of 7b with 6b. Comparison of the four
proposed transition state models in Figure 10 reveals that
the synclinal transition state XIIIsynclinal might be favored.
However, steric interactions between the tert-butyl di-
methylsilyl ether of aldehyde 7b and the chelated SnCl4
must increase the energy of this pathway.
FIGURE 7. Proposed transition states for the SnCl4- and BF3‚
OEt2-catalyzed [3 + 2]-annulations of 6b and the 2,5-cis-
disubstituted tetrahydrofuryl aldehyde 7b.
chelate structure dissociates greatly impacts the stereo-
selectivity of Lewis acid catalyzed carbonyl allylation
reactions. In the case of 7b, this equilibrium may allow
7bnonchelate to form due to ring strain associated with the
25
bicyclo[3.3.0] ring system formed in structure 7bchelate
.
It may also be that 7bchelate is destabilized by interactions
between the CR side chain and the ligands on tin. The
structure of the chelation-controlled transition state itself
may be more complicated than is indicated by XCram. The
fact that the alkoxy group adjacent to the aldehyde in
7b is tethered to the main chain through the tetrahy-
drofuran ring may prevent the bidentate chelate formed
between the aldehyde and SnCl4 from approaching
planarity, as is normally expected for chelated R-alkoxy
carbonyl compounds.26 Thus, the ring oxygen of 7b could
effectively become an additional chiral center and dia-
stereomeric forms of transition state structure XCram
would result. It is important to note that the favored
transition state XFelkin is also likely more complex. Specif-
ically, a 2:1 complex between 7b and SnCl4 should be
(24) (a) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281.
(b) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51,
5478.
(25) Chang, S.; McNally, D.; Shary-Tehrany, S.; Hickey, S. M. J.;
Boyd, R. H. J. Am. Chem. Soc. 1970, 92, 3109.
(26) Reetz, M. T.; Harms, K.; Reif, W. Tetrahedron Lett. 1988, 46,
5881.
(27) (a) Denmark, S. E.; Henke, B. R.; Weber, E. J. Am. Chem. Soc.
1987, 109, 2512. (b) Keck, G. E.; Andrus, M. B.; Castellino, S. J. Am.
Chem. Soc. 1989, 111, 8136.
8044 J. Org. Chem., Vol. 70, No. 20, 2005

[3 + 2]-Annulation Reactions of Chiral Allylsilanes and Aldehydes
FIGURE 10. Proposed transition states for the SnCl4-
catalyzed [3 + 2]-annulation reaction of 6a and the 2,5-cis-
tetrahydrofuryl aldehydes 7b and 7c.
FIGURE 9. Proposed transition states for the BF3‚OEt2-
catalyzed [3 + 2]-annulation reaction of 6a and the 2,5-cis-
disubstituted tetrahydrofuryl aldehyde 7b.
stereomer which we were not otherwise able to access.
It is possible that additional modifications to 7a or 7b
might lead to further diversity in the bis-tetrahydrofuran
structures available from our [3 + 2]-annulation ap-
proach.
Our finding that SnCl4 annulation reactions of the
acetate protected 2,5-cis-tetrahydrofuryl aldehyde 7c
with 6a resulted in a reversal in stereoselectivity was
intriguing. Formation of the cis-threo-cis structure 8f
likely occurs through a synclinal transition state struc-
ture XIIIsynclinal (Figure 10). Such a dramatic change in
the preferred reaction pathway must result from reduc-
tion of the steric bulk of the protecting group R to the
In conclusion, we have obtained a better understanding
of the scope of double stereodifferentiating [3 + 2]-an-
nulation reactions of chiral allylsilanes with 2-tetrahy-
drofuryl aldehydes. Our iterative approach provides
access to six diastereomeric bis-tetrahydrofuran struc-
tures 8a-f related to the core subunits of several bis-
tetrahydrofuran Annonaceous acetogenins, including the
trans-threo-trans series (e.g., asimicin and bullatacin), the
trans-erythro-cis series (e.g., trilobacin and trilobin), and
the cis-threo-cis series (e.g., squamocin N). The [3 +
2]-annulation reactions of the 2,5-trans-tetrahydrofuryl
aldehyde 7a with a stereochemically matched allylsilane
6a was stereodivergent with respect to SnCl4 and BF3‚
OEt2 Lewis acids, in accordance with our previous results
involving achiral aldehydes. The other [3 + 2]-annulation
reactions, including all reactions involving the 2,5-cis-
tetrahydrofuryl aldehyde 7b were stereoconvergent with
respect to Lewis acid. These results serve to highlight
the challenge of reagent versus substrate control in
double stereodifferentiating reactions as well as the
importance of the aldehyde structure in bidentate che-
lation-controlled carbonyl additions. Applications of these
results to the total synthesis of other members of the
Annonaceous acetogenin family will be reported in due
course.
tetrahydrofuran ring, as shown by 7bchelate and 7cchelate
.
This altered steric environment, or possibly a distorted
conformation, of 7c relative to 7b likely translates into
changes in the relative energy of possible transition
states available to 7c and 6a.
Our results indicate that the discreet interplay of steric
effects in the [3 + 2]-annulation reaction can modify the
stereoselectivity of reactions involving double stereodif-
ferentiation. In the case of 8c, we have used this to our
advantage by employing a modest structural change in
our substrate to synthesize a bis-tetrahydrofuran dia-
J. Org. Chem, Vol. 70, No. 20, 2005 8045

Mertz et al.
Experimental Section28
and CH2Cl2 (0.65 mL) was added BF3‚OEt2 (0.030 mL, 0.24
mmol). The mixture was stirred at -78 °C for 6 h. The yellow-
orange reaction mixture was quenched cold by dropwise
addition of Et3N (0.150 mL), and the resulting mixture was
warmed to room temperature. EtOAc (10 mL) and 10 mL of
saturated aqueous NaHCO3 were added to form a suspension
which was stirred at room temperature for 12 h. The organic
layer was removed, and the aqueous layer was extracted with
5 mL of EtOAc. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated to provide a yellow
oil. Purification of the crude product by silica gel chromatog-
raphy (10% Et2O-hexanes stepped to 15% Et2O-hexanes)
provided 8b (126 mg, 64%) as a clear oil: [R]24.0D ) -2.5 (c 2.8,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.48 (m, 2H), 7.37-7.31
(m, 3H), 3.87 (dd, J ) 9.8, 1.7 Hz, 1H), 3.83 (q, J ) 8.0 Hz,
1H), 3.73 (td, J ) 8.1, 6.1 Hz, 1H), 3.64 (td, J ) 5.4, 2.7 Hz,
1H), 3.48 (m, 1H), 3.28 (ddd, J ) 8.3, 5.1, 1.5 Hz, 1H), 2.07
(ddd, J ) 12.5, 8.3, 2.9 Hz, 1H), 1.99 (m, 1H), 1.86 (m, 2H),
1.72 (m, 2H), 1.66 (m, 1H), 1.54 (m, 1H), 1.40-1.17 (m, 1H),
0.89 (t, J ) 6.8 Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 0.87 (s, 9H),
0.86 (s, 9H), 0.332 (s, 3H), 0.330 (s, 3H), 0.02 (s, 3H), 0.00 (s,
3H), -0.03 (s, 3H), -0.05 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 138.0, 134.1, 129.4, 128.1, 83.2, 82.8, 81.2, 80.4, 75.5, 73.4,
35.2, 32.9, 32.8, 32.3, 30.1, 30.1, 29.9, 29.86, 29.81, 29.6, 27.8,
26.3, 26.2, 26.0, 25.8, 24.4, 22.9, 18.6, 18.4, 14.3, -3.8, -3.9,
-4.0, -4.0, -4.1, -4.5; IR (thin film, NaCl) 2927, 2855, 1472,
1472, 1251, 1073, 835, 774 cm-1; HRMS (ESI) m/z calcd for
C50H96O4Si3 (M + Na)+ 867.6514, obsd 867.6509. Anal. Calcd
for C50H96O4Si3: C, 71.02; H, 11.44. Found: C, 71.13; H, 11.56.
Representative Procedure for the Chelate-Controlled
(SnCl4-Promoted) Double-Asymmetric [3 + 2]-Annula-
tion Reaction: (2R,2′R,4′R,5R,5′S)-4′-(Dimethylphenyl-
silanyl)-5,5′-bis[(1R)-1-(tert-butyldimethylsilanyloxy)-
undecyl]octahydro-2,2′-bifuran (8a). To a 0 °C solution of
7a (87 mg, 0.23 mmol), 6a (189 mg, 0.41 mmol), 4 Å molecular
sieves (5 mg), and CH2Cl2 (0.80 mL) was added tin(IV)
tetrachloride (0.040 mL, 0.22 mmol). The mixture was stirred
at 0 °C for 3 h. The yellow-orange reaction mixture was
quenched at 0 °C by dropwise addition of Et3N (0.20 mL), and
the resulting mixture was warmed to room temperature.
EtOAc (5 mL) and 5 mL of saturated aqueous NaHCO3 were
added to form a cloudy white suspension which was stirred at
room temperature for 12 h. The organic layer was removed,
and the aqueous layer was extracted with 5 mL of EtOAc. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and evaporated to provide a yellow oil. Purification
of the crude product by silica gel chromatography (2.5% Et2O-
hexanes stepped to 5% Et2O-hexanes) provided 8a (98 mg,
51%) as a clear oil: [R]23.0 ) +2.0 (c 1.6, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 7.49 (m, 2H), 7.37-7.31 (m, 3H), 3.91 (dd,
J ) 8.8, 1.8 Hz, 1H), 3.91 (m, 1H), 3.80 (m, 2H), 3.61 (m, 1H),
3.29 (ddd, J ) 7.3, 5.9, 1.8 Hz, 1H), 1.84 (m, 3H), 1.68-1.54
(m, 5H), 1.46 (m, 4H), 1.35-1.16 (m, 42H), 0.89 (m, 6H), 0.88
(s, 19H), 0.321 (s, 3H), 0.316 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H),
0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.4,
134.0, 129.3, 128.0, 83.0, 82.3, 81.3, 75.0, 74.9, 34.7, 32.5, 31.8,
30.1, 29.9, 29.6, 28.8, 26.5, 26.3, 26.2, 26.1, 22.9, 18.5, 18.4,
14.3, -3.7, -3.8, -3.9, -4.1, -4.3; IR (thin film, NaCl) 2955,
2855, 1463, 1251, 1111, 1070, 835, 774 cm-1; HRMS (ESI) m/z
calcd for C50H96O4Si3 (M + Na)+ 867.6514, observed 867.6539.
Representative Procedure for the BF3‚OEt2-Promoted
Acknowledgment. Funding of this work by the
National Institutes of Health (GM038907) and a post-
doctoral fellowship (E.M.) from the National Cancer
Institute (CA103507) is gratefully acknowledged.
Double-Asymmetric [3
+ 2]-Annulation Reactions:
(2R,2′S,4′R,5R,5′S)-4′-(Dimethylphenylsilanyl)-5,5′-bis-
[(1R)-1-(tert-butyldimethylsilanyloxy)undecyl]octahydro-
2,2′-bifuran (8b). To a -78 °C solution of 7a (90 mg, 0.234
mmol), 6a (160 mg, 0.35 mmol), 4 Å molecular sieves (5 mg),
Supporting Information Available: Experimental de-
tails and 1H NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Complete experimental details are provided in the Supporting
Information.
JO0511290
8046 J. Org. Chem., Vol. 70, No. 20, 2005